JP2001525843A - Method for producing deoxyuridine derivative - Google Patents

Abstract

  (57) [Summary] Converting 2 ', 3'-O-isopropylidene-5-fluorouridine to the corresponding 5'-O-sulfonyl derivative, followed by reacting with an alkali metal or alkaline earth metal iodide; A method for producing 5'-deoxy-5-fluorouridine, comprising reducing the 5'-deoxy-5'-iodo-5-fluorouridine thus obtained after hydrolysis of the isopropylidene group. Is disclosed.

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD The present invention deoxyuridine derivatives, process for the preparation of deoxyuridine derivatives. More particularly, the present invention relates to 5'-deoxy-5-fluorouridine and a process for the preparation of novel intermediates useful in this process. The compound 5'-deoxy-5-fluorouridine is a well-known cytostatic, as will be indicated below by its International Nonproprietary Name doxiffluridine. Doxyfluridine with formula I is No. 4,071,680, which discloses a multi-step synthesis starting from 5-fluorouridine and involving removal of the 5'-hydroxy group through the corresponding 5'-iodine derivative. Is also disclosed. According to this document, the replacement of the 5'-hydroxy group by an iodine atom requires triphenylphosphite as a chemical iodinating agent, which requires particular attention due to the toxicity of the reagent due to the presence of reaction by-products. This is achieved by using meso-iodide. EP 21,231 discloses the preparation of doxyfluridine by removal of the acyl group from the corresponding 2 ', 3'-diester with a carboxylic acid, especially the corresponding 2', 3'-diacetate. I have. However, the synthesis of the starting material involves the replacement of the hydroxy group by a bromine atom and the conversion of the bromine derivative to the corresponding deoxy compound by catalytic hydrogenation. Also in this case, the bromination is carried out using a fluorescent compound, ie with bromine in the presence of large amounts of triphenylphosphine. S. Aymera and P.M. V. According to a paper by Danenberg (J. Med. Chem. 1982, 25, p. 999), 5′-deoxy-5′-iodo-2 ′, 3′-O-isopropylidene-5-fluorouridine is Prepared according to the method of Cook et al. (J. Med. Chem. 1979, 22, 1330, corresponding to U.S. Pat. No. 4,071,680). The same article describes the conversion of 5'-deoxy-5'-O-mesyloxy-2 ', 3'-O-isopropylidene-5-fluorouridine by lithium bromide to 5'-bromo-5'-deoxy-2', It discloses converting to 3'-O-isopropylidene-5-fluorouridine, but does not disclose any further conversion. On the other hand, in EP 21 231, cited above, the replacement of a bromine atom by a hydrogen atom is carried out under strong conditions, ie on catalytic hydrogenation in the presence of potassium hydroxide on a substrate not containing a uracil moiety. Wherein one is introduced after the production of the deoxysugar in the presence of a strong inorganic base. If the hydroxy group of 2 ', 3'-isopropylidene-5-fluorouridine is preactivated, such as a sulfonic ester, simply use sodium iodide in the absence of any fluorescent compound. It has now been found that the iodine atom can replace the hydroxyl group of 2 ', 3'-isopropylidene-5-fluorouridine. The iodine atom of 5'-deoxy-5'-iodo-2 ', 3'-O-isopropylidene-5-fluorouridine can be replaced by a hydrogen atom by catalytic hydrogenation without using a strong base. Thus, it has also been found that the corresponding 5'-deoxy compounds are obtained in very good yields. The same substitution can take place with other hydrogen donors, for example cyclohexene, cyclohexadiene or hydrides, for example tributyltin hydride. Thus, (a) 2 ′, 3′-O-isopropylidene-5-fluorouridine of formula II Is a functional derivative of a sulfonic acid of formula III Wherein R is (C ₁ -C ₄ ) alkyl, trifluoromethyl, an unsubstituted phenyl group, or a mono-, di- or tri-substituted phenyl group. 5'-sulfonyloxy derivatives of the formula IV thus obtained (Where R is the same as above) with an alkali metal iodide or an alkaline earth metal iodide, (c) 5′-deoxy-5′- of formula V thus obtained Iodo-2 ', 3'-O-isopropylidene-5-fluorouridine Is hydrolyzed in an acidic medium, and (d) 5'-deoxy-5'-iodo-5-fluorouridine of formula VI It is an object of the present invention to provide a process for the preparation of 5'-deoxy-5-fluorouridine, which comprises subjecting to a reduction with hydrogen or a hydrogen donor. In Formula III, R is preferably methyl, ethyl, n-butyl, trifluoromethyl, phenyl, monosubstituted phenyl, i.e., phenyl monosubstituted by methyl, methoxy, nitro or halogen, disubstituted. Phenyl, ie, phenyl disubstituted by two methyl groups, or phenyl trisubstituted, ie, phenyl trisubstituted by three methyl groups, especially phenyl 2,4,6-trisubstituted . Chloride, acid anhydrides or mixed acid anhydrides are suitably used as functional derivatives of the sulfonic acids. Methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride and 2,4,6-trimethylphenylsulfonyl chloride are particularly preferred as esterifying agents. Thus, in step (a), preferably the functional derivative of the sulfonic acid of formula III selected from the group consisting of those defined above is 2 ′, 3′-O-isopropylidene-5- React with fluorouridine. Advantageously, the reaction is carried out in an organic solvent, i.e. a halogenated solvent such as dichloromethane, 1,2-dichloroethane or 1,1,1-trichloroethane, or a polar aprotic solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide or acetonitrile, or ethyl acetate or an aromatic hydrocarbon, such as toluene or xylene, in a base such as trimethylamine, triethylamine, diisopropylamine, N-ethyl-diisopropylamine, pyridine or dimethyl Performed in the presence of aminopyridine. Usually, after 5-6 hours at a temperature of 0 ++ 40 ° C., the reaction is complete, and the compound of formula IV thus obtained is treated with water followed by simple filtration of the reaction by-products. Separated from things. The 5'-sulfonyloxy derivative of formula IV can be recovered by extraction with an organic solvent, followed by concentration, and can be isolated and characterized according to conventional methods. Alternatively, a concentrated solution of the compound of formula IV may be used directly for step (b). Step (b) comprises reacting the compound of formula IV in pure form or as said concentrated solution obtained at the end of step (a) with a ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone, ether, Preferably alkali or alkaline earth in an organic solvent such as dioxane or tetrahydrofuran or a polar aprotic solvent, preferably acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide. The treatment is carried out simply using an antideide. After 4-6 hours at a temperature of 40-80 ° C., the reaction is complete, as in step (a), by-products of the reaction are removed by filtration and washed with water. The expected end product, i.e., 5'-deoxy-5'-iodo-2 ', 3'-O-isopropylidene-5-fluorouridine of formula V, is recovered using an organic solvent, preferably ethyl acetate. , Then concentrated and isolated according to conventional methods. As in step (a), the concentrated solution containing the compound of formula V may be used directly for step (c). Step (c) comprises 5′-deoxy-5′-iodo-2 ′, 3′-O-isopropylidene-5-fluorouridine, according to methods customary in the field of sugar chemistry, more particularly in the field of nucleosides. In an acidic medium. Preferably, the hydrolysis is carried out in aqueous formic acid or, more advantageously, in aqueous acetic acid or in N, N-dimethylformamide or N, N-dimethylacetamide, in aqueous hydrogen chloride. At 80-100 ° C in the presence of The 5'-deoxy-5'-iodo-5-fluorouridine of formula VI thus obtained is isolated by evaporating the solvent, and the compound is recovered by extraction from a suitable solvent, preferably ethyl acetate. You. As mentioned above, the compounds obtained at the end of steps (a) and (b) may be isolated and identified, or preferably, they are isolated, neat, or solvent May be used in the form of a solution or suspension. The yields of the three steps are very high, i.e. always greater than 90% of theory, and the compound of the formula VI has the starting material 2 ', 3'-O-isopropylidene-5-fluorouridine of the formula II Based on the calculation, it can be recovered as high as 83-85%. In step (d), the compound of formula VI is subjected to a reduction, which is carried out by catalytic hydrogenation or using cyclohexane or cyclohexadiene as a hydrogen donor, for example as a catalyst, preferably with 5% Pd / C Or in the presence of hydrides. The reduction is carried out in an organic solvent, for example in an alcohol, for example methanol, ethanol, propanol, isopropanol or n-butanol or a mixture thereof. Preferably, an organic base such as trimethylamine, triethylamine, diisopropylamine, N-ethyldiisopropylamine, pyridine, dimethylaminopyridine, morpholine, N-methylmorpholine, 2-picoline, and quinone, or an inorganic base such as alkali bicarbonate Salts, such as sodium bicarbonate or potassium bicarbonate, are present in the reaction mixture. If the reduction is carried out with hydrogen, the hydrogenation takes place at room temperature or at a pressure of 1-2 bar and room temperature in the presence of 5% Pd / C. If the reduction is carried out in the presence of a hydrogen donor, for example cyclohexane, cyclohexadiene or a hydride, for example tributyltin hydride, the reaction is carried out in an alcoholic solvent, for example methanol, ethanol, isopropanol, n-butanol, It is carried out in isobutanol or the like, or in a mixture of the above solvent and an aprotic solvent, for example, toluene. More particularly, if the reduction is carried out at 60-90 ° C. with cyclohexane or cyclohexadiene as hydrogen donor, it is complete after 3-6 hours. The 5'-deoxy-5-fluorouridine thus obtained is isolated according to conventional methods, more particularly by filtering the catalyst and evaporating the solvent. The final product is crystallized using an ethanol / isopropanol = 3/2 (vol / vol) mixture. When the reduction is carried out using tributyltin hydride, the reaction is carried out by dissolving 5′-deoxy-5′-iodo-5-fluorouridine in an alcohol, for example methanol, and adding the reducing agent in an organic solvent. For example, in toluene, and the reaction mixture is heated to reflux in the presence of a catalytic amount of α, α′-azoisobutyronitrile. After 1-3 hours, the reaction is complete, and after evaporation of the solvent, the 5'-deoxy-5-fluorouridine thus obtained is recovered according to conventional methods. According to a preferred embodiment of the invention, steps (a), (b) and (c) are performed without isolation of the product obtained at the end of each of steps (a) and (b). In this way, the method of the invention makes it possible to prepare doxifluridine very easily and in very high yields. In addition, the method may be performed in a one-pot technique for steps (a), (b) and (c). The method is depicted in Scheme I, wherein R is (C ₁ ~C ₄₎ alkyl, trifluoromethyl, unsubstituted or mono-, - di - is or tri-substituted phenyl. Scheme 1 The following examples illustrate the invention without limiting it. Example 1 To a solution of 80 g (0.26 m) of 2 ', 3'-O-isopropylidene-5-fluorouridine in 700 ml of pyridine, cooled to about + 5 ° C, 90.6 g (0.48 m) of p -Toluenesulfonyl chloride was added. The resulting mixture was stirred for 5 hours, then 10 liters of water were added slowly, and the aqueous suspension was stirred for 3 hours. The mixture was left at room temperature for 15 hours, then the precipitate was filtered, washed with water and dried. The crystalline form of 2 ', 3'-O-isopropylidene-5'-O- (p-toluenesulfonyl) -5-fluorouridine was thus obtained. M. p. = 154-156 ° C; purity (HPLC) = 99.89% and [α] _D = + 26.71 ° (c = 1, CH ₃ OH). The product thus obtained is crystallized using ethanol to obtain a white crystalline powder. M.p. = 156-158 ° C; purity = 99.9-100% (HPL C). Example 2 A. 5'-Deoxy-5'-iodo-5-fluorouridine A solution of 39.2 g (0.13 m) of 2 ', 3'-O-isopropylidene-5-fluorouridine in 55 ml of methylene chloride and 159 ml (1.98 m) of pyridine was prepared. After cooling to + 5 ° C, 60 g (0.315 m) of p-toluenesulfonyl chloride are added. When the thus obtained mixture is stirred for 5 hours, formation of a large amount of precipitate is observed. Then 160 ml of methylene chloride and 160 ml of water are added therein, whereby the temperature rises to 40 ° C. The phases are separated and the organic phase is extracted with about 900 ml of 1N HCl. The organic phase is then washed with 2 × 100 ml of water. An oily residue was obtained from an organic phase containing 0.117 m of 2 ', 3'-O-isopropylidene-5'-O- (p-toluenesulfonyl) -5-fluorouridine (yield: 90% of theory). Concentrate under reduced pressure until complete and take up in 2 × 100 ml of acetone. The oily residue is dissolved in 600 ml of acetone and 105 g (0.70 m) of sodium iodide are added to the solution. The mixture is heated under reflux for 5 hours, then cooled and concentrated under reduced pressure, and the residue thus obtained is taken up in 2 × 80 ml of ethyl acetate. The residual oil is treated with 800 ml of ethyl acetate and 100 ml of water. The phases are separated and the aqueous layer is treated with 2.times.80 ml of ethyl acetate. The combined organic phases are washed with 2.times.100 ml of a 5% aqueous solution of sodium metabisulfite and then with 100 ml of water. The organic phase containing 0.113 m of 5'-deoxy-5'-iodo-2 ', 3'-O-isopropylidene-5-fluorouridine (yield: 97% of theory) is depressurized to a small volume. Concentrate. To the residue is added 560 ml of 80% aqueous acetic acid and the mixture is heated to 95 ° C. After heating for 4 hours, confirmation by HPLC is performed (0.34% residual starting material). After cooling, the mixture is concentrated in vacuo until an oily residue is obtained, which is taken up in 150 ml of ethyl acetate. The mixture is left at 20-25 ° C. for 15 hours. The product is filtered, washed with ethyl acetate and dried at 45 ° C. under reduced pressure. Thus, 44.5 g of 5'-deoxy-5'-iodo-5-fluorouridine are obtained. Melting point = 174-175 ° C, purity (HPLC) = 99.74% and [α] _D = + 8.96 ° (c = 1, CH ₃ OH). The mother liquor is concentrated under reduced pressure and the residue is taken up in 50 ml of ethyl acetate. After 15 hours at + 5 ° C., an additional 3.3 g of product is obtained. Total yield: 83% of theory. B. 5'-Deoxy-5-fluorouridine To a suspension of 20 g (0.053 m) of 5'-deoxy-5'-iodo-5-fluorouridine in a mixture of 60 ml of ethanol and 40 ml of isopropanol was added 15.2 ml (0.108 m) of the suspension. Diisopropylamine is added, then 3 g of 5% Pd / C are added therein and the mixture is hydrogenated at a pressure of about 1 bar for 14 hours. After filtering off the catalyst, the solution is concentrated under reduced pressure until a solid residue is obtained, which is crystallized from a mixture of ethanol / isopropanol = 60/40 v / v. After 8 hours, the product is filtered, washed with the mixture and dried at 45 ° C. for 15 hours. This gives 11.6 g (yield: 89% of theory) of 5'-deoxy-5-fluorouridine. Mp = 187~188 ℃, purity (HPLC) = 99.75% and _{[α] D = + 18.2 °} (c = 0.42, H 2 O). Example 3 40 g (0.087 m) of 2 ', 3'-O-isopropylidene-5'-O- (p-toluenesulfonyl) -5-fluorouridine obtained as described in Example 1 in 1700 ml of acetone 105 g of sodium iodide are added to the solution therein and the clear solution thus obtained is heated under reflux for 4-5 hours. Then the mixture is cooled, filtered and washed with acetone. The acetone solution is collected, concentrated under reduced pressure, and the residue is taken up in 3500 ml of ethyl acetate. After washing with 500 ml of a 3% aqueous solution of sodium metabisulfite and then with water, the ethyl acetate solution is concentrated to a small volume. After 15 hours, the precipitate is filtered and dried, giving 33.2 g of 5'-deoxy-5'-iodo-2 ', 3'-O-isopropylidene-5-fluorouridine as a white crystalline powder. Mp = 199-202 ° C., purity (HPLC) = 99.9% and _{[α] D = -16.8 ° (} c = 0.50, CH 3 OH). Example 4 A. 5'-Deoxy-5'-iodo-5-fluorouridine 51 g of 5'-deoxy-5'-iodo-2 ', 3'-O-isopropylidene-5-fluorouridine in 500 ml of acetic acid and 120 ml of water (0.105 m ) Is heated at 95 ° C. for 90 minutes. The solution thus obtained is concentrated under reduced pressure, the residue is taken up in 2 l of ethyl acetate and then concentrated to a small volume, after 15 hours at room temperature, the precipitate is filtered, washed with ethyl acetate and dried. This gives 35.6 g of 5'-deoxy-5'-iodo-5-fluorouridine. Mp = 174.5 to 175.5 ° C., purity (HPLC) = 99.74% and _{[α] D = + 8.96 °} (c = 1.00, CH 3 OH). B. 5'-Deoxy-5-fluorouridine To a solution of 35.1 g (0.078 m) of 5'-deoxy-5'-iodo-5-fluorouridine and 2.93 g of α, α'-azoisobutyronitrile in 1100 ml of methanol. A solution of 37.4 g of tributyltin hydride in 310 ml of toluene is added. The mixture is heated under reflux for 2 hours and the clear solution thus obtained is concentrated under reduced pressure until a semi-solid residue is obtained, which is dispersed in 900 ml of petroleum ether. The solid is filtered and treated with 1200 ml of water. The tin salt is filtered off, and the filtrate is concentrated under reduced pressure. The residue is crystallized from 500 ml of hot ether to give 12.3 g of 5'-deoxy-5-fluorouridine. Mp = 188~189 ℃, purity (HPLC) = 99.91% and _{[α] D = + 18.4 °} (c = 0.42, H 2 O). Example 5 To a suspension of 10 g (0.026 m) of 5'-deoxy-5'-iodo-5-fluorouridine obtained as described in step A of Example 2 in 100 ml of n-butanol was added 6 Add ml of cyclohexene (0.06 m) and 14 ml (0.1 m) of triethylamine. The mixture is heated to 60 ° C. to achieve complete dissolution, then 1.5 g of 5% Pd / C is added therein. The suspension is heated at 80 ° C. for 5 hours, filtered at the same temperature by washing with hot n-butanol and concentrated under reduced pressure until a residue is obtained, which is crystallized from a mixture of 60 ml of ethanol and 40 ml of isopropanol. Let it. This gives 4.5 g of 5'-deoxy-5-fluorouridine. Mp = 188~1 89 ℃, purity (HPLC) = 99.87% and _{[α] D = 18.35 ° (} c = 0.42, H 2 O).

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, L S, MW, SD, SZ, UG, ZW), EA (AM, AZ , BY, KG, KZ, MD, RU, TJ, TM), AL , AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, E E, ES, FI, GB, GE, GH, GM, GW, HU , ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, M D, MG, MK, MN, MW, MX, NO, NZ, PL , PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, U Z, VN, YU, ZW (72) Inventor Monki Aldini, Simone             Italy, 21100 Barese, Via Mar             Kobi, 10 (72) Inventor Aldanini, Giancarlo             21039 Bedero Barcubi, Italy             A, Locita Carbola (No address)

Claims (1)

[Claims] 1. (A) 2 ', 3'-O-isopropylidene-5-fluorouridine of formula II Is a functional derivative of a sulfonic acid of formula III Wherein R is (C ₁ -C ₄ ) alkyl, trifluoromethyl, an unsubstituted phenyl group, or a mono-, di- or tri-substituted phenyl group. 5'-sulfonyloxy derivatives of the formula IV thus obtained (Where R is the same as above) with an alkali metal iodide or an alkaline earth metal iodide, (c) 5′-deoxy-5′- of formula V thus obtained Iodo-2 ', 3'-O-isopropylidene-5-fluorouridine Is hydrolyzed in an acidic medium, and (d) 5'-deoxy-5'-iodo-5-fluorouridine of formula VI Of formula I comprising subjecting to a reduction with hydrogen or a hydrogen donor The method for producing 5′-deoxy-5-fluorouridine of the above. 2. In the derivative of the sulfonic acid of the formula III, R is methyl, ethyl, n-butyl, trifluoromethyl, phenyl or phenyl mono-substituted by methyl, methoxy, nitro group or halogen or other mono-substituted phenyl Phenyl or other disubstituted phenyl disubstituted by two methyl groups, or phenyl or other trisubstituted phenyl substituted by 2,4,6-trimethyl or other methyl groups 2. The method of claim 1 wherein the method is phenyl. 3. 2. The process according to claim 1, wherein in step (a) chloride, an acid anhydride or a mixed acid anhydride is used as the functional derivative of the sulfonic acid of the formula III. 4. 4. The method according to claim 3, wherein the functional derivative of the acid of formula III is methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride or 2,4,6-trimethylphenylsulfonyl chloride. 5. 2. The method according to claim 1, wherein steps (a), (b) and (c) are performed without isolating the product obtained at the end of each of steps (a) and (b). 6. The method of claim 1 wherein the reduction in step (d) is performed by catalytic hydrogenation. 7. 7. The method according to claim 6, wherein palladium on activated carbon is used as a catalyst. 8. 7. The method of claim 6, wherein said catalytic hydrogenation is performed in the presence of a base. 9. 9. The method according to claim 8, wherein said base is a secondary or tertiary amine. 10. 10. The method according to claim 9, wherein the secondary or tertiary amine is trimethylamine, triethylamine, diisopropylamine, N-ethyldiisopropylamine, pyridine, dimethylaminopyridine, morpholine, N-methylmorpholine, 2-picoline or quinoline. The described method. 11. 9. The method according to claim 8, wherein said base is sodium bicarbonate, potassium bicarbonate or another inorganic base. 12. 7. The method according to claim 6, wherein tributyltin hydride is used as the reducing agent. 13. 13. The method according to claim 12, wherein the reduction is performed in the presence of a catalytic amount of α, α'-azoisobutyronitrile. 14． 7. The method according to claim 6, wherein the reduction is carried out using cyclohexene or cyclohexadiene as hydrogen donor. 15. 15. The method according to claim 14, wherein said reducing step is performed at a temperature of 60-90C.